PROJECT SUMMARY Neuroinvasive alpha-herpesviruses such as herpes simplex virus (HSV) and pseudorabies virus (PRV) cause a broad range of diseases in humans and other animals and are significant causes of morbidity and mortality. Novel strategies to interfere with the virion structural rearrangements required for infectivity could prove valuable to treat infections, yet critical aspects of the virion architecture and its metastability remain poorly defined. In this application, we outline a strategy to identify dynamic protein interactions within extracellular viral particles. The proposed research will test the hypothesis that conditional interactions between the essential viral protein pUL36 and capsids contribute to critical steps in infection including viral disassembly and regulation of pUL36 deubiquitinase activity: processes required for alpha-herpesviruses to establish life-long infection of the nervous system.